1. Field of the Invention
The present invention relates to the field of indwelling medical devices, in particular catheters, as well as to the field of methods and compositions for flushing, locking, priming, and coating these medical devices. The invention also relates to pharmaceutical preparations useful in increasing catheter flow and preventing infection in catheters with the potential for fibrin deposition or with preexisting fibrin-bound clots.
2. Description of Related Disclosures
Delivery systems are widely used in medicine as a means for introducing liquid material that might include medicaments, nutrition, or other active agents to a particular locus in a patient. Such systems frequently involve the use of catheters, which, for many applications, are surgically or intravenously located and stitched into place for long-term administration of the desired material. Typical systems include central catheters such as may be used for total parenteral nutrition (TPN) used in, e.g., short bowel syndrome (for the duration of life), with the risk of sepsis or endocarditis. Such systems also include catheters and drains that are involved in peritoneal dialysis for those with terminal kidney failure, which, if infected, can lead to peritonitis with serious consequences.
Intravascular catheters are among the most commonly used medical devices. Such catheters are routinely placed into a patient's vascular system for many procedures and often are left in place for extended periods. One type of delivery system used for some years in the treatment of conditions in humans comprises a reservoir or chamber of small volume subcutaneously implanted under the fascia having direct access via a catheter to the cardiovascular system. Such systems are known as port systems. Since a port and an intravascular catheter are direct paths from the outside environment to the patient's bloodstream, the presence of the catheter or port presents a substantial and continuous potential for introduction of microorganisms into the patient's bloodstream.
It is now generally acknowledged that indwelling catheterization in medical, surgical, gynecological, urological and other patients can lead to serious infection of the urogenital tract. Practitioners have developed many protocols related to placement, use, attachment and detachment of fluid-handling devices and other procedures related to catheters. The goal of almost all of these procedures is to avoid introduction of a microorganism into the patient's bloodstream.
A number of methods for reducing the risk of infection have been developed that incorporate anti-infective agents into medical devices, none of which have been clinically proven to be completely satisfactory. Such devices desirably provide effective levels of anti-infective agent during the entire period that the device is being used. This sustained release may be problematic to achieve, in that a mechanism for dispersing anti-infective agent over a prolonged period of time may be required, and the incorporation of sufficient amounts of anti-infective agent may adversely affect the surface characteristics of the device. The difficulties encountered in providing effective anti-microbial protection increase with the development of drug-resistant pathogens.
The current standard care of vascular catheters includes flushing the lumen of the catheter with an anti-coagulant, such as heparin, to prevent blood in and around the tip of the catheter from coagulating and obstructing the flow of fluids through the catheter. Furthermore, heparin has no anti-microbial activity, and, in addition, if not carefully controlled, it can carry the anti-coagulation process too far, thereby presenting a risk of hemorrhage. Heparin can also result in antibody formation, leading to a serious autoimmune condition of heparin-induced thrombocytopenia (HIT), which depletes platelets and further increases risk of bleeding. Thus, infections, as well as thrombotic occlusion, continue to occur frequently despite the prophylactic use of heparin flushes. Knowledge of the pathogenesis and microbiology of central venous catheter-related infections is essential to provide effective prevention of this problem.
Staphylococcus epidermidis and S. aureus account for 75% of central venous catheter (CVC)-related infections. Candida species account for another 10% to 15% of such infections. The use of anti-staphylococcal antibiotics to prevent these infections has been found to reduce CVC-related bacterial infections, but only at the expense of the occurrence of higher rates of fungal (Candida) infections.
There is also an observed correlation between thrombogenesis and infection. Essentially, a fibrin sheath that subsequently acts to cover the internal and external surfaces of a catheter engulfs indwelling vascular catheters. This fibrin sheath provides such organisms as Staphylococci and Candida with an enhanced adherence capacity to the catheter surface. Unlike these particular microbes, gram-negative bacilli do not adhere well to fibrin and fibronectin. A composition that halted fibrin formation would thus be particularly useful in preventing the colonization of Staphylococci, Candida, and the like, at indwelling catheter sites.
When a medicament is introduced into a patient through a catheter, the practitioner commonly follows the introduction with a flush solution that may include an anticoagulant such as heparin. The purpose of the flush solution is to move the medicament out of the catheter so that the entire dosage is delivered, and to leave a residual fill in the catheter so that the patient's blood does not back up in the catheter and possibly form a clot that would occlude the bore of the catheter. Thus, when the catheter is subsequently needed again, the properly flushed catheter is likely fully patent and ready for the next usage.
Root et al., Antimicrob. Agents Chemother., 32: 1627-1631 (1988) published a study that reported on the effect in catheters of disodium ethylene diamine tetraacetic acid (EDTA), a compound well known for its chelating properties in vivo and widely used as an anticoagulant in vitro. U.S. Pat. No. 5,363,754 disclosed that pharmaceutical compositions of a mixture of minocycline and EDTA were useful in maintaining the patency of a catheter port. U.S. Pat. No. 5,091,442 described tubular articles, such as condoms and catheters, which are rendered anti-microbially effective by the incorporation of a non-ionic sparingly soluble anti-microbial agent, such as triclosan. The anti-microbial agent may be distributed throughout the article, or in a coating thereon. U.S. Pat. No. 5,362,754 disclosed a pharmaceutical preparation that includes minocycline and EDTA for maintaining the patency of a catheter. U.S. Pat. No. 5,362,754 reported the use of a mixture of minocycline and EDTA (M-EDTA) to maintain the patency of a catheter port.
Purchase et al., Nephron, 58: 119-20 (1991) disclosed use of calcium chelators, including citrate, for this purpose. Butuovic et al., Artif. Organs. 22: 945-7 (1998) disclosed that citrate and polygeline, which is a plasma substitute made from cow bones, were equally as effective as heparin in maintaining the catheter. In a talk presented at the 30th annual meeting of the American Society of Nephrology, held Nov. 2-5, 1997 in San Antonio, Tex., Sodemann et al. reported that the replacement of catheters due to infection can be avoided by routine application of the concentrated gentamicin/citrate mixture.
However, one citrate calcium chelator for dialysis catheters, designated TRICITRASOL™, has certain drawbacks. Some patients reported dysgensia for a short period immediately after the injection of citrate. Recently the FDA reported a case of a patient who died shortly after the injection of citrate as a catheter lock (Stas et al., Nephrol Dial Transplant, 16: 1521-1522 (2001); FDA issues warning on triCitrasol (trademark) dialysis catheter anticoagulant. FDA Talk Paper T00-16, 14 April 2000.
U.S. Pat. No. 5,019,096 disclosed infection-resistant medical devices comprising a synergistic combination of a silver salt (such as silver sulfadiazine) and chlorhexidine. U.S. Pat. No. 5,772,640 reported on polymeric medical articles comprising the anti-infective agents, chlorhexidine and triclosan. U.S. Pat. No. 5,362,754 disclosed preventing glycocalyx formation on a catheter by coating with EDTA and/or minocycline, preventing bacterial and fungal infections. U.S. Pat. No. 6,258,797 disclosed combating infection or sepsis in catheter and port systems by using an anti-microbial locking solution of taurolidine or taurultam.
U.S. Pat. No. 6,166,007 disclosed anti-microbial locks comprising taurinamide derivatives and carboxylic acids and/or salts thereof for preventing infection and blood coagulation in or near a medical prosthetic device after the device has been inserted in a patient. EP 1,040,841 described prevention of thrombosis formation and/or bacterial growth on a liquid-contacting surface of a delivery system by contacting the surface with a thrombosis-preventing liquid having anti-coagulant agent, taurolidine, and/or taurultam. EP 882,461 disclosed a medical device having both physiological and anti-microbial activity comprising a base material, a crosslinked coating film formed on a surface of the base material, and each of a physiologically active substance and an anti-microbial substance bonded to the coating film.
Boorgu et al., ASAIO J., 46 (6): 767-770 (Nov. 2000) published on an adjunctive antibiotic/anticoagulant lock therapy in the treatment of bacteremia associated with the use of a subcutaneously implanted hemodialysis access device. Attached to the device are two catheters that are implanted into the superior vena cava or right atrium. An antibiotic/anticoagulant lock therapy entailed the instillation of both an antibiotic and an anticoagulant into the device. See also Schwartz et al., Journal of Clinical Oncology., 8(9):1591-1597 (1990) and Kamal et al., JAMA, 265(18):2364-2368 (1991).
Wiernikowski et al., Am J. Pediatr Hematol Oncol. 13(2): 137-140 (1991) disclosed that bacteriostatic saline flush solutions prevented catheter infections compared to normal saline. Vercaigne et al., Pharmacotherapy, 20: 394-9 (2000) evaluated heparin plus antibiotics as a locking solution to prevent infection. Patel et al., Thromb Hemost, 82: 1205-6 (1999) disclosed successful use of low-dose r-hirudin for recurrent dialysis catheter thrombosis in a patient with heparin-induced thrombocytopenia. Darouiche et al., Nutrition, 13(4)(suppl): 26S-29S (1997) reported that the prevention of vascular catheter-related infection can be achieved using anti-microbial agents involving the application of topical disinfectants such as chlorhexidine, use of silver-impregnated subcutaneous cuffs (for short-term CVCs), flushing of catheters with a combination of anti-microbial and anti-thrombotic agents, and coating of catheters with either antiseptic (chlorhexidine and silver sulfadiazine) or anti-microbial agents (minocycline and rifampin).
Antibacterial lock solutions have been used to clean out catheters. For example, U.S. Pat. No. 6,174,537 disclosed a catheter flush solution. See also Sodermann et al. Blood Purif., 19: 251-254 (2001) on DIALOCK™ and CLS; the TUBEX™ Heparin Lock Flush Solution (Wyeth-Ayerst); and Henrickson et al., J. Clin Oncol., 18: 1269-1278 (2000) on prevention of CVC-related infections and thrombotic events using vancomycin/cipro-floxacin/heparin flush solution.
Soft-cuffed, implantable CVCs such as the QUINTON PERMCATH™ CVC (Quinton Instrument Co., Seattle, Wash.) are increasingly used in patients with end-stage renal disease as a means of permanent access. Their major limitations, besides infection, are thrombosis and inadequate blood flow. To prevent those complications, heparin is conventionally used for priming the QUINTON PERMCATH™ CVC between dialysis sessions. Schenk et al., Amer. J. Kidney Diseases, 35: 130-136 (Jan. 2000) showed that recombinant tissue-plasminogen activator (rt-PA) was superior to heparin for priming the QUINTON PERMCATH™ CVC between hemodialysis sessions. However, Schenk et al. utilized 2 mg of alteplase plus SWFI (sterile water for injection, USP), which does not prevent growth of bacteria.
Central venous access device (CVAD) occlusions or blockages due to formation of a blood clot (thrombus) within or at the tip of the CVAD catheter are a common problem that can block the administration of therapies to patients. Estimates suggest that 25% of CVADs become occluded, with thrombosis as the most common etiology (Haire et al., Thromb. Haemost, 72: 543-547 (1994); Rubin, J. Clin. Oncol., 1: 572-573 (1983); Lokich et al., J. Clin. Oncol., 3: 710-717 (1985)). In 1994, Haire et al., supra, performed a double-blind, prospective, randomized trial of urokinase versus alteplase (t-PA) in dysfunctional catheters proven radiographically to be occluded by thrombus. Catheters were treated with 2 mg of alteplase or 10,000 U of urokinase that was allowed to dwell in the device for 2 hours. After up to two treatments, alteplase restored function in more catheters than urokinase (89% versus 59% (p=0.013)).
On Sep. 4, 2001 the U.S. Food and Drug Administration (FDA) approved the thrombolytic agent CATHFLO™ ACTIVASE® (alteplase) t-PA, for the restoration of function to CVADs, as assessed by the ability to withdraw blood. CATHFLO™ ACTIVASE® t-PA is available in a 2-mg, single-patient-use vial, is the only marketed thrombolytic available for this indication, and offers medical professionals a viable treatment option for a CVAD complication that can hinder patient care. One vial of CATHFLO™ t-PA contains 2.2 mg of alteplase, 77 mg of L-arginine, 0.2 mg of POLYSORBATE 80™ emulsifier, and phosphoric acid to adjust the pH to approximately 7.3.
T-PA has been bonded to other materials than vascular catheters. See, for example, Zhou et al., J. Control Release, 55: 281-295 (1998); Greco et al., Ann Vasc. Surg, 9: 140-145 (1995) and Woodhouse et al., Biomaterials, 17: 75-77 (1996).
U.S. Pat. No. 5,688,516 disclosed use of selected combinations of a chelating agent, anticoagulant, or anti-thrombotic agent, with a non-glycopeptide anti-microbial agent, such as the tetracycline antibiotics, to coat a medical device and to inhibit catheter infection. Preferred combinations include minocycline or another non-glycopeptide anti-microbial agent together with EDTA, EGTA, DTPA, TTH, heparin, and/or hirudin in a pharmaceutically acceptable diluent. U.S. Pat. No. 6,187,768 similarly disclosed use of an anti-microbial agent and an anticoagulant, an anti-thrombotic agent, or a chelating agent to maintain the patency of indwelling medical devices such as catheters and for preventing infections caused by bacterial growth in catheters.
Notwithstanding the above-described contributions to the art, a need continues to exist for a non-toxic method for removal of fibrin-bound blood clots from catheters, especially indwelling medical devices. There is a further need for the prevention and the removal of fibrin from such devices, as certain bacteria have binding sites that favor sticking to fibrin, in particular.